This invention relates to a class of spirocyclic ketone compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are 3-spiro-cyclopentanone piperidine derivatives.
International (PCT) patent specification no. WO 97/49710 (published Dec. 31st, 1997) discloses spiro-piperidine derivatives as substance P antagonists. In particular, WO 97/49710 relates to spirocyclic piperidine derivatives containing a 1-oxa-7-aza-spiro[4.5]decane core.
We have now found a further class of non-peptides which are potent antagonists of tachykinins, especially of the neurokinin-1 (substance P) receptor.
The present invention provides compounds of the formula (I): 
wherein
R1 represents hydroxy, C1-6alkyl, fluoroC1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C1-6alkoxyC1-4alkyl, C1-6aralkoxyC1-4alkoxy, fluoroC1-6alkoxyC1-4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, phenoxy, cyano, halogen, NRaRb, SRa, SORa, SO2Ra, OSO2Ra, NRaCOR14, CORa, CO2Ra or CONRaRb where Ra and Rb each independently represent hydrogen, C1-4alkyl or fluoroC1-4alkyl;
R2 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy;
or when R2 is adjacent to R1, they may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen and sulphur, which ring is optionally substituted by a group selected from C1-4alkyl, CF3, xe2x95x90O or xe2x95x90S;
R3 represents hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, cyano, SRa, SORa, SO2Ra, NRaRb, NRaCOR14, CORa, CO2Ra, CONRaRb or C1-4alkyl substituted by cyano, CO2Ra or CONRaRb where Ra and Rb are as previously defined;
or R3 represents a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, trifluoromethyl, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, phenyl, xe2x80x94(CH2)rNRaRb, xe2x80x94(CH2)rNRaCORb, xe2x80x94(CH2)rCONRaRb, or CH2C(O)Ra, where Ra and Rb are as previously defined and r is zero, 1 or 2;
R4 represents hydrogen, halogen, C1-6alkyl, C1-6alkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, where Ra and Rb are as previously defined;
R5 represents hydrogen, halogen, C1-6alkyl, CF3 or C1-6alkoxy substituted by C1-4alkoxy;
R6 represents hydrogen, CORa, CO2Ra, COCONRaRb, COCO2Ra, C1-6alkyl optionally substituted by a group selected from (CO2Ra, CONRaRb, hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONHphenyl(C1-4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaC1-6alkylR12, CONR13C2-6alkenyl, CONR13C2-6alkynyl, COCONRaRb, CONRaC(NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from C1-6alkyl, C1-6alkoxy, halogen and trifluoromethyl);
or R6 represents a group of the formula xe2x80x94CH2Cxe2x89xa1CCH2NR7R8 where R7 and R8 are as defined below;
or R6 represents C1-6alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by xe2x95x90O or xe2x95x90S and optionally substituted by a group of the formula ZNR7R8 where
Z is C1-6alkylene or C3-6cycloalkyl;
R7 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R8 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NRc moiety where Rc is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R9 and R10 each independently represent hydrogen, halogen, C1-6alkyl, CH2ORe, oxo, CO2Ra or CONRaRb where Ra and Rb are as previously defined and Re represents hydrogen, C1-6alkyl or phenyl;
R12 represents ORa, CONRaRb or heteroaryl;
R13 represents hydrogen or C1-6alkyl; and
R14 represents C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl or phenyl;
and pharmaceutically acceptable salts thereof.
According to a first aspect of the present invention, phenyl ring A is preferably a 2,5-disubstituted phenyl ring.
According to a second alternative aspect of the present invention, phenyl ring A is preferably a 3,5-disubstituted phenyl ring.
A preferred class of compound of formula (I) is that wherein R1 is hydroxy, C1-6alkyl, fluoroC1-6alkyl, C2-6alkenyl, C1-6alkoxy, fluoroC1-6alkoxy, C2-6alkeny oxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, cyano, NRaRb, SRa, OSO2Ra, or R1 together with the group R2 form a 5-membered saturated ring containing one oxygen atom.
A particularly preferred class of compound of formula (I) is that wherein R1 is C1-6alkyl, fluoroC1-6alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C3-7cycloalkoxy or C3-7cycloalkoxyC1-4alkyl, especially methyl, trifluoromethyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, cyclopropoxy or cyclopropylmethoxy.
Another preferred class of compound of formula (I) is that wherein R2 is a hydrogen, fluorine or chlorine atom, especially a hydrogen atom.
A further preferred class of compound of formula (I) is that wherein R3 is hydrogen, halogen, fluoroC1-6alkyl, fluoroC1-6alkoxy, cyano, NRaRb, NRaCOR14 (where R14 is preferably methyl, methoxy, trifluoromethyl or phenyl), or a 5-membered aromatic heterocyclic group as previously defined.
Also preferred is the class of compound of formula (I) in which R3 is C1-6alkyl, fluoroC1-6alkyl, fluoroC1-6alkoxy or a 5-membered aromatic heterocyclic group as previously defined, especially methyl, trifluoromethyl, trifluoromethoxy or 5-trifluoromethyl-1,2,3,4-tetrazol-1-yl.
Certain particularly apt compounds of the present invention include those wherein R3 is a group selected from pyrrole, furan, thiene, pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, triazine, and tetrazole, each heteroaryl group being optionally substituted as previously defined.
Preferred compounds of the present invention are those wherein R3 is a group selected from furan, pyridine, pyrazole, imidazole, oxazole, isoxazole, pyrazine, pyrimidine, thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and tetrazole, each heteroaryl group being optionally substituted as previously defined.
Particularly preferred compounds of the present invention are those wherein R3 is a group selected from furan, pyridine, pyrimidine, 1,2,3-triazole, 1,2,4-triazole and tetrazole, each heteroaryl group being optionally substituted as previously defined.
An especially preferred class of compound of formula (I) is that wherein R3 is the group 
where R11 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, (CH2)rCONRaRb, (CH2)rNRaRb or (CH2)rNRaCORb, where Ra and Rb are hydrogen or C1-4alkyl, and r is zero, 1 or 2.
Another especially preferred class of compound of formula (I) is that wherein R3 is the group 
wherein R11 is as previously defined.
Another especially preferred class of compound of formula (I) is that wherein R3 is the group 
wherein R11 is as previously defined.
R11 is preferably hydrogen, C1-4alkyl, especially methyl, CF3, (CH2)rCONRaRb, SORa or SO2Ra where Ra, Rb and r are as previously defined. Most especially, R11 is CF3.
A further preferred class of compound of formula (I) is that wherein R4 is a hydrogen atom or a fluorine atom.
Another preferred class of compound of formula (I) is that in which R5 is a hydrogen atom.
A further preferred class of compound of formula (I) is that wherein R6 is a C1-6alkyl group, in particular CH2, CH(CH3) and CH2CH2 and especially CH2, substituted by a 5-membered heterocyclic ring containing 2 or 3 nitrogen atoms as previously defined.
In particular, the 5-membered ring is a heterocyclic ring selected from: 
Another preferred class of compound of formula (I) is that wherein one of R9 and R10 is hydrogen, and especially wherein R9 and R10 are both hydrogen atoms.
One favoured group of compounds of the present invention are of the formula (Ia) and pharmaceutically acceptable salts thereof: 
wherein
R2, R4 and R6 are as defined in relation to formula (I);
R1a is C1-4alkoxy, fluoroC1-4alkoxy, C3-5cycloalkoxy or C3-5cycloalkoxyC1-2alkyl; and
R3a is fluoroC1-4alkoxy.
R1a is preferably methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, cyclopropoxy or cyclopropylmethoxy.
R3a is preferably trifluoromethoxy.
Another favoured group of compounds of the present invention are of the formula (Ib) and pharmaceutically acceptable salts thereof: 
wherein
R4 and R6 are as defined in relation to formula (I);
R1b is C1-4alkyl, or fluoroC1-4alkyl; and
R3b is C1-4alkyl or fluoroC1-4alkyl.
R1b is preferably methyl or trifluoromethyl. Most especially R1b is trifluoromethyl.
R3b is preferably methyl or trifluoromethyl. Most especially R3b is trifluoromethyl.
Most preferably, R1b and R3b are the same.
With respect to compounds of the formula (I), Z (where present), may be a linear, branched or cyclic group. Favourably Z contains 1 to 4 carbon atoms and most favourably 1 or 2 carbon atoms. A particularly favourable group Z is CH2.
With respect to compounds of the formula (I), R7 may aptly be a C1-4alkyl group or a C2-4alkyl group substituted by a hydroxyl or C1-2alkoxy group, R8 may aptly be a C1-4alkyl group or a C2-4alkyl group substituted by a hydroxyl or C1-2alkoxy group, or R7 and R8 may be linked so that, together with the nitrogen atom to which they are attached, they form an azetidinyl, pyrrolidinyl, piperidyl, morpholino, thiomorpholino, piperazino or piperazino group substituted on the nitrogen atom by a C1-4alkyl group or a C2-4alkyl group substituted by a hydroxy or C1-2alkoxy group.
Where the group NR7R8 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring contains a double bond, a particularly preferred group is 3-pyrroline.
Where the group NR7R8 represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and preferably between 7 and 10, ring atoms. Suitable rings include 5-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl, 6-azabicyclo[3.2.2]decyl, 7-azabicyclo[4.3.1]decyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.
Where R8 represents a C2-4alkyl group substituted by a 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S, suitable rings include pyrrolidino, piperidino, piperazino, morpholino, or thiomorpholino. Particularly preferred are nitrogen containing heteroaliphatic rings, especially pyrrolidino and morpholino rings.
Particularly suitable moieties ZNR7R8 include those wherein Z is CH2 or CH2CH2 and NR7R8 is amino, methylamino, dimethylamino, diethylamino, azetidinyl, pyrrolidino and morpholino.
In particular, Z is preferably CH2 and NR7R8 is preferably dimethylamino, azetidinyl or pyrrolidino, especially dimethylamino.
When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term xe2x80x9calkylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
As used herein, the terms xe2x80x9cfluoroC1-6alkylxe2x80x9d and fluoroC1-6alkoxyxe2x80x9d means a C1-6alkyl or C1-6alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Similarly, the term xe2x80x9cfluoroC1-4alkylxe2x80x9d means a C1-4alkyl group in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroC1-3alkyl and fluoroC1-3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCH2CF3.
The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.
Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
As used herein, the terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.
As used herein, the term xe2x80x9cheteroarylxe2x80x9d as a group or part of a group means a 5- or 6-membered heteroaromatic ring containing 1 to 4 heteroatoms selected from N, O and S. Particular examples of such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, and tetrazolyl.
When used herein the term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
Specific compounds within the scope of this invention include:
(3RS,5RS,6SR)-3-(2-methoxy-5-trifluoromethoxy)phenyl-6-phenyl-7H-azaspiro[4.5]decan-1-one;
(3RS,5RS,6SR)-3-(2-methoxy-5-trifluoromethoxy)phenyl-6-phenyl-7-(1,2,4-triazol-3-yl)methyl-7-azaspiro[4.5]decan-1-one;
(3RS,5RS,6SR)-3-(2-cyclopropoxy-5-trifluoromethoxy)phenyl-6-phenyl-7-azaspiro[4.5]decan-1-one;
(3SR,5RS,6SR)-3-(2-cyclopropoxy-5-trifluoromethoxy)phenyl-6-phenyl-7-azaspiro[4.5]decan-1-one;
(3RS,5RS,6SR)-3-(2-cyclopropoxyoxy-5-trifluoromethoxy)phenyl-6-phenyl-7-(1,2,4-triazol-3-yl)methyl-7-azaspiro[4.5]decan-1-one;
(3SR,5RS,6SR)-3-(2-methoxy-5-trifluoromethoxy)phenyl-6-phenyl-7H-azaspiro[4.5]decan-1-one;
(3RS,5RS,6SR)-3-(2-isopropoxy-5-trifluoromethoxy)phenyl-6-phenyl-7-azaspiro[4,5]decan-1-one;
(3RS,5RS,6SR)-3-(2-isopropoxy-5-trifluoromethoxy)phenyl-6-phenyl-7-(1,2,4-triazol-3-yl)methyl-7-azaspiro[4,5]decan-1-one;
(3RS,5RS,6SR)-3-(2-hydroxy-5-trifluoromethoxy)phenyl-6-phenyl-7-azaspiro[4,5,]decan-1-one;
(3RS,5RS,6SR)-3-(2-cyclopropylmethyloxy-5-trifluoromethoxy)phenyl-6-phenyl-7-azaspiro[4,5,]decan-1-one;
(3RS,5RS,6SR)-3-(2-difluoromethoxy-5-trifluoromethoxy)phenyl-6-phenyl-7-azaspiro[4,5]decan-1-one;
(3RS,5RS,6SR)-3-(2-difluoromethoxy-5-trifluoromethoxy)phenyl-6-phenyl-7-(1,2,4-triazol-3-yl)methyl-7-azaspiro[4,5]decan-1-one;
(3RS,5RS,6SR)-6-phenyl-3-(2-(2,2,2-trifluoroethoxy-5-trifluoromethoxy)phenyl-7-azaspiro[4,5,]decan-1-one;
(3RS,5RS,6SR)-6-phenyl-7-(1,2,4-triazol-3-yl)methyl-3-(2-(2,2,2-trifluoroethoxy-5-trifluoromethoxy)phenyl-7-azaspiro[4,5]decan-1-one;
(3SR,5RS,6SR)-3-(3,5-dimethyl)phenyl-6-phenyl-7-azaspiro[4,5]decan-1-one;
(3SR,5RS,6SR)-3-(3,5-dimethyl)phenyl-6-phenyl-7-(1,2,4-triazol-3-yl)methyl-7-azaspiro[4,5]decan-1-one;
(3RS,5RS,6SR)-3-(3,5-bis(trifluoromethyl))phenyl-6-phenyl-7-azaspiro[4,5]decan-1-one;
(3RS,5RS,6SR)-3-(3,5-bis(trifluoromethyl))phenyl-6-phenyl-7-(1,2,4-triazol-3-yl)methyl-7-azaspiro[4,5]decan-1-one;
(3SR,5RS,6SR)-3-(2-difluoromethoxy-5-trifluoromethoxy)phenyl-6-phenyl-7-azaspiro[4,5]decan-1-one;
(3SR,5RS,6SR)-3-(2-difluoromethoxy-5-trifluoromethoxy)phenyl-6-phenyl-7-(1,2,4-triazol-3-yl)methyl-7-azaspiro[4,5]decan-1-one;
(3RS,5RS,6SR)-3-(2-difluoromethoxy-5-(5-(trifluoromethyl)tetrazolyl))phenyl-6-phenyl-7-azaspiro[4,5]decan-1-one;
(3SR,5RS,6SR)-3-(2-difluoromethoxy-5-(5-trifluoromethyl)tetrazolyl)phenyl-6-phenyl-7-azaspiro[4,5]decan-1-one;
(3RS,5RS,6SR)-3-(2,6-dimethyl)phenyl-6-phenyl-7-azaspiro[4,5]decan-1-one;
and pharmaceutically acceptable salts thereof.
In a further aspect of the present invention, the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
For use in medicine, the salts of the compounds of formula (1) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the xe2x80x9cparent drugxe2x80x9d or xe2x80x9cparent moleculexe2x80x9d) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
The compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The preferred compounds of the formula (I), (Ia) and (Ib) will have the stereochemistry of the 5- and 6-positions that is possessed by the compound of Example 1 (i.e. 5-(R) and 6-(S)). Thus for example as shown in formula (Ic) 
It will be appreciated that the preferred definitions of the various substituents recited herein may be taken alone or in combination and, unless otherwise stated, apply to the generic formula for compounds of the present invention as well as to the preferred classes of compound represented by formula (Ia), formula (Ib) and formula (Ic).
The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include those comprising a compound of formula (I), as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The present invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises bringing a compound of formula (I) into association with a pharmaceutically acceptable carrier or excipient.
The compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity.
Thus, for example, an excess of tachykinin, and in particular substance P, activity is implicated in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; delerium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer""s disease, senile dementia, dementia of the Alzheimer""s type, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson""s disease, Huntington""s disease, Pick""s disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson""s disease and other extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour; substance-related disorders arising from the use of alcohol, amphetamines (or amphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, intoxication, withdrawal, intoxication delerium, withdrawal delerium, persisting dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders; epilepsy; Down""s syndrome; demyelinating diseases such as MS and ALS and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid haemorrhage or cerebral oedema.
Tachykinin, and in particular substance P, activity is also involved in nociception and pain. The compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pain predominates, including soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, episiotomy pain, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low back pain; sciatica; ankylosing spondylitis, gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; ophthalmic conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganglioblastomas and small cell carcinomas such as small cell lung cancer.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, Crohn""s disease, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo, dizziness and Meniere""s disease, surgery, migraine, variations in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; plasma extravasation resulting from cytokine chemotherapy, disorders of bladder function such as cystitis, bladder detrusor hyper-reflexia and incontinence; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, vascular headache, migraine and Reynaud""s disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine.
The compounds of formula (I) are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting.
The compounds of formula (I) are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula (I) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy, and emesis induced by other pharmacological agents, for example, rolipram.
Examples of such chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.
Particular examples of chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and Vomiting: Recent Research and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Fla., USA (1991) pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al in Cancer Treatment Reports (1984) 68(1), 163-172].
The compounds of formula (I) are also of use in the treatment of emesis induced by radiation including radiation therapy such as in the treatment of cancer, or radiation sickness; and in the treatment of post-operative nausea and vomiting.
It will be appreciated that the compounds of formula (I) may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate or sequential use for the relief of emesis. Such combined preparations may be, for example, in the form of a twin pack.
A further aspect of the present invention comprises the compounds of formula (I) in combination with a 5-HT3 antagonist, such as ondansetron, granisetron or tropisetron, or other anti-emetic medicaments, for example, a dopamine antagonist such as metoclopramide or domperidone or GABAB receptor agonists such as baclofen. Additionally, a compound of formula (I), either alone or in combination with one or more other anti-emetic therapeutic agents, may be administered in combination with an anti-inflammatory corticosteroid, such as dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, flunisolide, budesonide, or others such as those disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712. Dexamethasone (Decadron(trademark)) is particularly preferred. Furthermore, a compound of formula (I) may be administered in combination with a chemotherapeutic agent such as an alkylating agent, antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as described above. In general, the currently available dosage forms of the known therapeutic agents for use in such combinations will be suitable.
Suitable methods for determining the anti-emetic effects of compounds of the present invention are well known in the art, for example, using the ferret model of cisplatin-induced emesis described by F. D. Tattersall et al, in Eur. J. Pharmacol., (1993) 250, R5-R6.
The compounds of formula (I) are also particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain.
The compounds of formula (I) are also particularly useful in the treatment of depression including depressive disorders, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder.
The present invention further provides a compound of formula (I) for use in therapy.
According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.
The present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I).
According to a further aspect of the present invention, it may be desirable to treat any of the aforementioned conditions with a combination of a compound according to the present invention and one or more other pharmacologically active agents suitable for the treatment of the specific condition. The compound of formula (I) and the other pharmacologically active agent(s) may be administered to a patient simultaneously, sequentially or in combination.
Thus, for example, for the treatment of respiratory diseases such as asthma, a compound of formula (I) may be used in conjunction with a bronchodilator, such as a xcex22-adrenergic receptor agonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula (I) and the bronchodilator may be administered to a patient simultaneously, sequentially or in combination.
Likewise, a compound of the present invention may be employed with a leukotriene antagonists, such as a leukotriene D4 antagonist such as a compound selected from those disclosed in European patent specification nos. 0 480 717 and 0 604 114 and in U.S. Pat. Nos. 4,859,692 and 5,270,324. This combination is particularly useful in the treatment of respiratory diseases such as asthma, chronic bronchitis and cough.
The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) and an effective amount of a bronchodilator.
The present invention also provides a composition comprising a compound of formula (I), a bronchodilator, and a pharmaceutically acceptable carrier.
It will be appreciated that for the treatment or prevention of migraine, a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5-HT1 agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
Likewise, for the treatment of behavioural hyperalgesia, a compound of the present invention may be used in conjunction with an antagonist of N-methyl D-aspartate (NMDA), such as dizocilpine.
For the treatment or prevention of inflammatory conditions in the lower urinary tract, especially cystitis, a compound of the present invention may be used in conjunction with an anti-inflammatory agent such as a bradykinin receptor antagonist.
The present invention also provides a composition comprising a compound of formula (I), a bronchodilator, and a pharmaceutically acceptable carrier.
It will be appreciated that for the treatment or prevention of pain or nociception, a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs and, in particular, opioid analgesics, especially morphine. Specific anti-inflammatory agents include diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam and sulindac. Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of pain or nociception.
It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents.
Suitable classes of anti-depressant agent include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, xcex1-adrenoreceptor antagonists and atypical anti-depressants.
Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof. Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.
Suitable selective serotonin reuptake inhibitors include: fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof.
Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof
Suitable reversible inhibitors of monoamine oxidase include: moclobemide, and pharmaceutically acceptable salts thereof.
Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venlafaxine, and pharmaceutically acceptable salts thereof.
Suitable CRF antagonists include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.
Suitable atypical anti-depressants include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof.
Suitable classes of anti-anxiety agent include benzodiazepines and 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists.
Suitable benzodiazepines include: alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereof.
Suitable 5-HT1A receptor agonists or antagonists include, in particular, the 5-HT1A receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an anti-depressant or anti-anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an anti-depressant or anti-anxiety agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of depression and/or anxiety.
It will be appreciated that for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents.
The present invention accordingly provides the use of a compound of formula (I) and an anorectic agent for the manufacture of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an anorectic agent, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) and an anorectic agent, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the compound of formula (I) and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of eating disorders. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a compound of formula (I) and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
Suitable anoretic agents of use in combination with a compound of the present invention include, but are not limited to, aminorex, amphechoral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
A particularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptble salts thereof.
Particularly preferred halogenated amphetamine derivatives of use in combination with a compound of the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.
It will be appreciated that for the treatment or prevention of obesity, the compounds of the present invention may also be used in combination with a selective serotonin reuptake inhibitor (SSRI).
The present invention accordingly provides the use of a compound of formula (I) and an SSRI for the manufacture of a medicament for the treatment or prevention of obesity.
The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an SSRI, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of obesity comprising a compound of formula (I) and an SSRI, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the compound of formula (I) and SSRI may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of obesity. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a compound of formula (I) and an SSRI as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of obesity.
Suitable selective serotonin reuptake inhibitors of use in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof.
As used herein xe2x80x9cobesityxe2x80x9d refers to a condition whereby a mammal has a Body Mass Index (BMI), which is calculated as weight per height squared (kg/m2), of at least 25.9. Conventionally, those persons with normal weight, have a BMI of 19.9 to less than 25.9.
The obesity herein may be due to any cause, whether genetic or environmental. Examples of disorders that may result in obesity or be the cause of obesity include overeating and bulimia, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich""s syndrome, Type II diabetes, GH-deficient subjects, normal variant short stature, Turner""s syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia.
xe2x80x9cTreatmentxe2x80x9d (of obesity) refers to reducing the BMI of the mammal to less than about 25.9, and maintaining that weight for at least 6 months. The treatment suitably results in a reduction in food or calorie intake by the mammal.
xe2x80x9cPreventionxe2x80x9d (of obesity) refers to preventing obesity from occurring if the treatment is administered prior to the onset of the obese condition. Moreover, if treatment is commenced in already obese subjects, such treatment is expected to prevent, or to prevent the progression of, the medical sequelae of obesity, such as, e.g., arteriosclerosis, Type II diabetes, polycycstic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
A further aspect of the present invention comprises the use of a compound of formula (I) for achieving a chronobiologic (circadian rhythm phase-shifting) effect and alleviating circadian rhythm disorders in a mammal. The present invention is further directed to the use of a compound of formula (I) for blocking the phase-shifting effects of light in a mammal.
The present invention further relates to the use of a compound of formula (I) for enhancing or improving sleep quality, in particular by increasing sleep efficiency and augmenting sleep maintenance, as well as for preventing and treating sleep disorders and sleep disturbances, in a mammal.
In a preferred embodiment, the present invention provides a method for the phase advance or phase delay in the circadian rhythm of a subject which comprises administering to the subject an appropriate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The present invention is further directed to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for enhancing or improving sleep quality as well as preventing and treating sleep disorders and sleep disturbances in a mammal. In particular, the present invention provides a method for enhancing or improving sleep quality by increasing sleep efficiency and augmenting sleep maintenance. In addition, the present invention provides a method for preventing and treating sleep disorders and sleep disturbances in a mammal which comprising the administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention is useful for the treatment of sleep disorders, including Disorders of Initiating and Maintaining Sleep (insomnias) (xe2x80x9cDIMSxe2x80x9d) which can arise from psychophysiological causes, as a consequence of psychiatric disorders (particularly related to anxiety), from drugs and alcohol use and abuse (particularly during withdrawal stages), childhood onset DIMS, nocturnal myoclonus and restless legs and non specific REM disturbances as seen in ageing.
As used herein the term xe2x80x9cmammalsxe2x80x9d includes animals of economic importance such as bovine, ovine, and porcine animals, especially those that produce meat, as well as domestic animals, sports animals, zoo animals, and humans, the latter being preferred.
It will be appreciated that when using any combination described herein, both the compound of formula (I) and the other active agent(s) will be administered to a patient, within a reasonable period of time. The compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term xe2x80x9ccombinationxe2x80x9d also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, one active component may be administered as a tablet and then, within a reasonable period of time, the second active component may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a xe2x80x9cfast dissolving oral formulationxe2x80x9d is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
By xe2x80x9creasonable period of timexe2x80x9d is meant a time period that is not in excess of about 1 hour. That is, for example, if the first active component is provided as a tablet, then within one hour, the second active component should be administered, either in the same type of dosage form, or another dosage form which provides effective delivery of the medicament.
The excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimising the risk of unwanted side effects.
In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of emesis, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of psychiatric disorders, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
According to a general process (A), compounds of formula (I) may be prepared by the reaction of a compound of formula (II) 
wherein R4, R5, R6, R9 and R10 are as defined in relation to formula (I), with a Grignard reagent of the formula (III) 
wherein R1, R2 and R3 are as defined in relation to formula (I) and Hal is a halogen atom, preferably bromine or chlorine. The reaction is preferably effected in the presence of a copper ion catalyst to increase 1,4 addition at the double bond. Suitable copper ion catalysts include copper(I)iodide, copper(I)chloride and copper(II)acetate.
Formation of the Grignard reagent of formula (III) is conveniently effected in situ by the reaction of the corresponding aryl halide with magnesium in a suitable solvent such as an ether, for example, tetrahydrofuran.
According to another general process (B), compounds of formula (I) may be prepared by the reduction of a compound of formula (IV): 
wherein R1, R2, R3, R4, R5, R6, R9 and R10 are as defined in relation to formula (I).
Suitable reducing conditions whereby the double bond is selectively reduced without affecting the carbonyl group include: sodium borohydride with a transition metal salt catalyst; hydrogen and a rhodium catalyst; tributyltin hydride and tetrakis(triphenylphosphine)palladium (0); and tributyltin hydride with copper(I)iodide and lithium chloride.
The selection of reducing agent may also be used to preferentially prepare the 3-position epimers. In particular, dissolving metal reduction using, for example, magnesium in methanol, may be used to prepare the 3-xcex2 epimer.
According to another general process (C), compounds of formula (I) may be prepared by the interconversion of a corresponding compound of formula (I) in which R6 is H, hereinafter referred to as formula (V) 
by reaction with a compound of formula (VI):
LGxe2x80x94R6axe2x80x83xe2x80x83(VI)
where R6a is a group of the formula R6 as defined in relation to formula (I) (other than H) or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine); and, if R6a is a precursor group, converting it to a group R6 (in which process any reactive group may be protected and thereafter deprotected if desired).
This reaction may be performed in conventional manner, for example in an organic solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate.
Suitable alternative methods for introducing the group R6 are described, for instance, in International Patent Specification No. WO 95/18124.
According to another general process (D), compounds of formula (I) wherein R1 is C1-6alkoxy, fluoroC1-6alkoxy, C2-6alkenoxy, C3-7cycloalkoxy, or C3-7cycloalkylC1-4alkoxy, may be prepared by the interconversion of a compound of formula (I) wherein R1 is hydroxy, hereinafter referred to as formula (VII) 
by reaction with an appropriate alkyl-, fluoroalkyl-, alkenyl-, cycloalkyl-, or cycloalkylalkyl-halide, especially the iodide, in the presence of a base.
Suitable bases include alkali metal hydrides, such as sodium hydride, in a suitable solvent such as dimethylformamide. The reaction is conveniently effected at about room temperature.
The compounds of formula (VII) are particularly useful where specific 3-position epimers are required since the phenols are generally separable by chromatography.
According to another general process (E), compounds of formula (I) may be prepared from a compound of formula (II) and a compound of formula (IV), where Hal in the compound of formula (IV) is chlorine, bromine or, preferably, iodine, by a reductive Heck reaction using a palladium catalyst such as palladium acetate with, for example, tri-o-tolylphosphine, dimethylformamide and tributylamine, or tetrabutylammonium chloride and dimethylformamide, and a reducing agent, preferably formic acid or a salt thereof, such as potassium formate.
According to another general process (F), compounds of formula (I) wherein R1 is cyclopropoxy may be prepared from a compound of formula (VIII): 
by reaction with lithium naphthalenide in tetrahydrofuran. The reaction is preferably effected at reduced temperature, for example at about xe2x88x9278xc2x0 C.
According to another general process (G), compounds of formula (I) wherein R6 is 1,2,4-triazol-3-ylmethyl, may be prepared from a compound of formula (V) and N-formyl-2-chloroacetamidhyrazone (Yangisawa, J. Med. Chem., 1984, 27:849) in the presence of a base.
Suitable bases of use in the reaction include alkali metal carbonates such as potassium carbonate. The reaction is conveniently effected in an anhydrous organic solvent such as anhydrous dimethylformamide, preferably at elevated temperature such as 60xc2x0 C. rising to between 100xc2x0 C. and 140xc2x0 C.
According to another general process (H), compounds of formula (I) wherein R6 is a 1,2,3-triazol-4-ylmethyl group substituted by CH2NR7R8, may be prepared by reaction of a compound of formula (IX) 
with an amine of formula NHR7R8, in a suitable solvent such as an ether, for example, dioxan, at elevated temperature, for example, at the reflux temperature of the solvent.
Further details of suitable procedures will be found in the accompanying Examples.
Compounds of formula (II) may be prepared by heating a compound of formula (X) 
wherein Ph is a phenyl group, in the presence of an organic base, preferably pyridine. The reaction is conveniently effected at reflux.
Compounds of formula (X) may be prepared by the oxidation and subsequent cyclisation of a compound of formula (XI) 
Oxidation is effected under conventional conditions using, for example, sodium periodate in a suitable solvent such as an alcohol, for example, methanol, optionally including water. The intramolecular cyclisation is conveniently effected using, for example, lithium bis(trimethylsilyl)amide. The reaction is preferably effected in an ether, for example, tetrahydrofuran, at reduced temperature, for example at about xe2x88x9278xc2x0.
Compounds of formula (XI) may be prepared by the reaction of a compound of formula (XII) 
with thiophenol in the presence of azaisobutyronitrile in a suitable solvent such as an aromatic hydrocarbon, for example toluene, conveniently at an elevated temperature, for example at about 80xc2x0 C.
Compounds of formula (XII) may be prepared by the reaction of a compound of formula (XIII) 
with allyl bromide. The condensation is conveniently effected in the presence of lithium bis(trimethylsilyl)amide. The reaction is preferably effected in an ether, for example, tetrahydrofuran, at reduced temperature, for example at about xe2x88x9278xc2x0 C.
Compounds of formula (XIII) may be prepared stepwise from 2-chloronicotinoyl chloride. Firstly, the corresponding methyl ester is prepared by conventional esterification, for example, by reaction with methanol in pyridine. Then the appropriate 2-aryl moiety is introduced by reaction of an appropriately substituted phenyl-trialkyltin derivative with the 2-chloro nicotinic acid methyl ester in the presence of lithium chloride and a transition metal catalyst such as tetrakis(triphenylphosphine)palladium (0). Suitable solvents for this step include aromatic hydrocarbons, for example toluene.
The resulting 2-arylnicotinic acid methyl ester is then reduced to the corresponding 2-arylnipecotic acid methyl ester using, for example, catalytic hydrogenation in the presence of palladium hydroxide and hydrochloric acid. This step is conveniently effected in a solvent such as an alcohol, for example methanol. The resultant compound is then conveniently N-protected on the piperidine nitrogen using, for example, a tertiary-butoxycarbonyl protecting group, before subsequent use.
Compounds of formula (III) may be prepared from known compounds or from aryl halide derivatives prepared by methods described herein or otherwise well-known in the published literature.
Compounds of formula (IV) are useful intermediates for the steroselective preparation of compounds of formula (I). Compounds of formula (IV) may be prepared by the reaction of a corresponding compound of formula (I) with lithium dialuminium hydride in tetrahydrofuran, followed by treatment with a phenylselenyl halide (chloride or bromide) to give a phenylselenide derivative which is then treated with hydrogen peroxide to give the compound of formula (VI). The elimination is preferably effected at 0xc2x0 C. rising to about room temperature. More preferably, benzeneseleninic anhydride may be used to afford the compound of formula (IV) in a single step.
Intermediates of formula (V) may be prepared, for example, in a similar manner to that descibed in general processes (A) and (B), preferably with an amino protecting group on the piperidine nitrogen in the compound of formulae (II) and (IV). Suitable amino protecting groups include alkoxycarbonyl groups such as tert-butoxycarbonyl and trichloroethoxycarbonyl, aralkyloxycarbonyl groups such as benzyloxycarbonyl, or aralkyl groups such as benzyl. Removal of the protecting group is effected by conventional procedures thus, for example, tert-butoxycarbonyl groups may be removed under acidic conditions using, for example, trifluoroacetic acid; tert-butoxycarbonyl groups, together with benzyloxycarbonyl and benzyl groups, may also be removed by hydrogenolysis in the presence of a catalyst, for example, palladium; and trichloroethoxycarbonyl groups may be removed with zinc dust.
Compounds of formula (VII) may be prepared from the appropriate phenolic precursor (or a protected (e.g. benzyloxy) derivative thereof) using, for example, the methods of processes (A), (B) or (C).
Compounds of formula (VIII) may be prepared from a compound of formula (VII) by reaction with (1-iodo-cycloprop-1-yl)phenylsulfide.
Compounds of formula (IX) may be prepared from a compound of formula (XIV) 
wherein Hal is a halogen atom, for example, chlorine, bromine or iodine, specially chlorine, by reaction with an azide, for example, sodium azide in a suitable solvent such as dimethylsulfoxide at or below room temperature.
Compounds of formula (XIV) may be prepared by a dropwise addition of a compound of formula (V) to a dihaloacetylene of formula Hal-CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2-Hal where each Hal is independently chlorine, bromine or iodine, especially chlorine. The reaction is conveniently effected in a suitable solvent such as dimethylformamide in the presence of a base such as potassium carbonate.
It will be appreciated that compounds of the formula (I) wherein R6 contains an xe2x95x90O or xe2x95x90S substituent can exist in tautomeric forms. All such tautomeric forms and mixtures thereof are included within this invention. Most aptly the xe2x95x90O or xe2x95x90S substituent in R6 is the xe2x95x90O substituent.
Where they are not commercially available, the intermediates of formula (IV) above may be prepared, for example, from the corresponding phenol derivative using, for example, the procedures described in the accompanying Examples, or by alternative procedures which will be readily apparent to one skilled in the art.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01165. The compounds were found to be active with IC50 at the NK1 receptor of less than 100 nM on said test method.
For the avoidance of doubt, the nomenclature adhered to throughout this specification is based upon the following structures: 